Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder for which there is no effective treatment or cure. The long term objective of part of the program project application is to develop new lines of human progenitors releasing growth factors that can be used in pre clinical studies towards a cell based therapy for ALS. The specific hypothesis is that progenitors engineered in vitro to produce growth factors will generate astrocytes when transplanted which then slow down or prevent motor neuron death in a rat model of ALS. This is based on extensive published data showing that there may be a primary deficit in astrocytes in both patients and rodent models of ALS and that growth factors can protect motor neurons from cell death. Our preliminary data shows that we can generate human neural progenitors that secretegrowth factors, and that these can survive, migrate and integrate into the spinal cord of the ALS rat, forming a human/rat chimera. Based on these observations the specific aims are 1. Improve and extend our current progress in protecting motor neurons in the ALS rat using novel approaches including regionally specified astrocytes, drugs to block inflammation, and species specific astrocytes. 2. Perform further experiments using new lines of progenitor cells releasing growth factors recently shown to have strong protective effects on motor neurons. 3. Extend our studies to the phrenic motor complex in collaboration with Dr. Mitchell (Project 1) and assess whether astrocytes releasing growth factors can prevent changes in respiration related to motor neuron loss. The results of these experiments will establish whether astrocyte transplants combined with growth factor delivery can ameliorate motor neuron death in a well established model of ALS. As such they constitute a highly relevant set of experiments to national health. The information will also be crucial to the other projects in this program - through providing growth factor secreting astrocytes to protect respiratory motor neurons (Project 1) and human motor neurons derived from ES cells (Project 3).